Antidepressants Slow to “Kick In” Because of Laggard G Proteins

Antidepressants known as selective serotonin reuptake inhibitors (SSRIs) not only interact with serotonin transporters, they also move G proteins out of lipid rafts in the cell membrane. Although the first process occurs within minutes, the second is much slower. In fact, the delay in G protein redistribution appears to account for why antidepressants take so long to begin working. [Molly Huttner]

It is common knowledge that antidepressants can take weeks or even months to start working. But it has been a mystery why antidepressants take so long to take effect. But now there is a ray of light in the darkness. The slowness with which antidepressants take effect has been correlated with the slowness of a mechanism quite apart from the binding of selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed antidepressants, with serotonin transporters. This binding can occur within minutes. SSRIs, it turns out, also act through another process, the redistribution of G proteins, the slowness of which correlates with the delay in lifting depression through SSRIs.

The new finding comes from researchers based at the University of Illinois at Chicago. These researchers, led by neuroscientist Mark Rasenick, Ph.D., long suspected that the delayed drug response involved certain signaling molecules in nerve cell membranes called G proteins. Previous research by Dr. Rasenick’s group showed that in people with depression, G proteins tended to congregate in lipid rafts, areas of the membrane rich in cholesterol. Stranded on the rafts, the G proteins lacked access to a molecule called cyclic adenosine monophosphate (cAMP), which they need in order to function. The dampened signaling could be why people with depression are “numb” to their environment, Dr. Rasenick reasoned.

In the lab, Dr. Rasenick bathed rat glial cells, a type of brain cell, with different SSRIs and located the G proteins within the cell membrane. He found that SSRIs accumulated in the lipid rafts over time—and as they did so, G proteins in the rafts decreased.

Details of this work appeared July 18 in the Journal of Biological Chemistry, in an article entitled, “Antidepressants Accumulate in Lipid Rafts Independent of Monoamine Transporters to Modulate Redistribution of the G protein, Gαs.”

“Since antidepressants appear to specifically modify Gαs localized to lipid rafts, we sought to determine whether structurally diverse antidepressants, accumulate in lipid rafts,” wrote the article’s authors. “Sustained treatment of C6 glioma cells, which lack 5HT [5-hydroxytryptamine, or serotonin] transporters, showed marked concentration of several antidepressants in raft fractions, as revealed by increased absorbance and by mass fingerprint.”

The scientists noted that closely related molecules that lacked antidepressant activity did not concentrate in raft fractions. Following up on this observation, the scientists determined that at least two classes of antidepressants accumulate in lipid rafts and effect translocation of Gαs to the nonraft membrane fraction where it activates the cAMP-signaling cascade.

“The process showed a time-lag consistent with other cellular actions of antidepressants,” said Dr. Rasenick. “It's likely that this effect on the movement of G proteins out of the lipid rafts toward regions of the cell membrane where they are better able to function is the reason these antidepressants take so long to work.”

“Determining the exact binding site could contribute to the design of novel antidepressants that speed the migration of G proteins out of the lipid rafts, so that the antidepressant effects might start to be felt sooner.”

The authors of the article concluded that analysis of the structural determinants of raft localization could not only help to explain the hysteresis of antidepressant action, but also lead to design and development of novel substrates for depression therapeutics.

Dr. Rasenick already knows a little about the lipid raft binding site. When he doused rat neurons with an SSRI called escitalopram and a molecule that was its mirror image, only the right-handed form bound to the lipid raft. “This very minor change in the molecule prevents it from binding,” explained Dr. Rasenick, “so that helps narrow down some of the characteristics of the binding site.”